PMID- 35605188
OWN - NLM
STAT- MEDLINE
DCOM- 20221031
LR  - 20221128
IS  - 1527-7755 (Electronic)
IS  - 0732-183X (Print)
IS  - 0732-183X (Linking)
VI  - 40
IP  - 31
DP  - 2022 Nov 1
TI  - Post Hoc Analysis of Lorlatinib Intracranial Efficacy and Safety in Patients With 
      ALK-Positive Advanced Non-Small-Cell Lung Cancer From the Phase III CROWN Study.
PG  - 3593-3602
LID - 10.1200/JCO.21.02278 [doi]
AB  - PURPOSE: Lorlatinib significantly improved progression-free survival (PFS) versus 
      crizotinib and showed robust intracranial activity in patients with previously 
      untreated advanced ALK-positive non-small-cell lung cancer (NSCLC) in the phase 
      III CROWN trial. Here, we report post hoc efficacy outcomes in patients with and 
      without brain metastases at baseline, and present data on the incidence and 
      management of CNS adverse events (AEs) in CROWN. METHODS: Eligible patients were 
      randomly assigned 1:1 to first-line lorlatinib (100 mg once daily) or crizotinib 
      (250 mg twice a day); no crossover between treatment arms was permitted. Tumor 
      assessments, including CNS magnetic resonance imaging, were performed at 
      screening and then at 8-week intervals. Regular assessments of patient-reported 
      outcomes were conducted. RESULTS: PFS by blinded independent central review was 
      improved with lorlatinib versus crizotinib in patients with and without brain 
      metastases at baseline (12-month PFS rates: 78% v 22% and 78% v 45%, 
      respectively). Lorlatinib was associated with lower 12-month cumulative incidence 
      of CNS progression versus crizotinib in patients with (7% v 72%) and without (1% 
      v 18%) brain metastases at baseline. In total, 35% of patients had CNS AEs with 
      lorlatinib, most of grade 1 severity. Occurrence of CNS AEs did not result in a 
      clinically meaningful difference in patient-reported quality of life. At 
      analysis, 56% of CNS AEs had resolved (33% without intervention; 17% with 
      lorlatinib dose modification), and 38% were unresolved; most required no 
      intervention. Lorlatinib dose modification did not notably influence PFS. 
      CONCLUSION: First-line lorlatinib improved PFS outcomes and reduced CNS 
      progression versus crizotinib in patients with advanced ALK-positive 
      non-small-cell lung cancer with or without brain metastases at baseline. Half of 
      all CNS AEs resolved without intervention or with lorlatinib dose modification.
FAU - Solomon, Benjamin J
AU  - Solomon BJ
AUID- ORCID: 0000-0003-3059-5730
AD  - Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
FAU - Bauer, Todd M
AU  - Bauer TM
AUID- ORCID: 0000-0002-3078-5043
AD  - Sarah Cannon Research Institute/Tennessee Oncology, PLLC, Nashville, TN.
FAU - Ignatius Ou, Sai-Hong
AU  - Ignatius Ou SH
AUID- ORCID: 0000-0002-1764-4975
AD  - University of California Irvine School of Medicine, Orange, CA.
FAU - Liu, Geoffrey
AU  - Liu G
AD  - Princess Margaret Cancer Centre, Toronto, Canada.
FAU - Hayashi, Hidetoshi
AU  - Hayashi H
AUID- ORCID: 0000-0001-8787-5587
AD  - Kindai University Faculty of Medicine, Osaka-Sayama, Osaka, Japan.
FAU - Bearz, Alessandra
AU  - Bearz A
AUID- ORCID: 0000-0003-1020-2338
AD  - Centro di Riferimento Oncologico, Istituto Nazionale Tumori, IRCCS, Aviano, 
      Italy.
FAU - Penkov, Konstantin
AU  - Penkov K
AD  - Private Medical Institution Euromedservice, St Petersburg, Russian Federation.
FAU - Wu, Yi-Long
AU  - Wu YL
AUID- ORCID: 0000-0002-3611-0258
AD  - Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital and 
      Guangdong Academy of Medical Sciences, Guangzhou, China.
FAU - Arrieta, Oscar
AU  - Arrieta O
AUID- ORCID: 0000-0002-1164-3779
AD  - Instituto Nacional de Cancerologia (INCan), Mexico City, Mexico.
FAU - Jassem, Jacek
AU  - Jassem J
AD  - Medical University of Gdansk, Gdansk, Poland.
FAU - Calella, Anna M
AU  - Calella AM
AD  - Pfizer Oncology, Milan, Italy.
FAU - Peltz, Gerson
AU  - Peltz G
AD  - Pfizer Oncology, Groton, CT.
FAU - Polli, Anna
AU  - Polli A
AD  - Pfizer Oncology, Milan, Italy.
FAU - Thurm, Holger
AU  - Thurm H
AD  - Pfizer Oncology, La Jolla, CA.
FAU - Mok, Tony
AU  - Mok T
AUID- ORCID: 0000-0002-8251-0551
AD  - State Key Laboratory of Translational Oncology, Chinese University of Hong Kong, 
      Shatin, Hong Kong.
LA  - eng
SI  - ClinicalTrials.gov/NCT03052608
PT  - Journal Article
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
DEP - 20220523
PL  - United States
TA  - J Clin Oncol
JT  - Journal of clinical oncology : official journal of the American Society of 
      Clinical Oncology
JID - 8309333
RN  - OSP71S83EU (lorlatinib)
RN  - 53AH36668S (Crizotinib)
RN  - EC 2.7.10.1 (Anaplastic Lymphoma Kinase)
RN  - 0 (Lactams, Macrocyclic)
RN  - 0 (Protein Kinase Inhibitors)
SB  - IM
CIN - J Clin Oncol. 2022 Nov 1;40(31):3564-3568. PMID: 35679525
MH  - Humans
MH  - *Carcinoma, Non-Small-Cell Lung/drug therapy/genetics
MH  - Crizotinib/adverse effects
MH  - Anaplastic Lymphoma Kinase
MH  - *Lung Neoplasms/drug therapy/genetics
MH  - Quality of Life
MH  - Lactams, Macrocyclic/adverse effects
MH  - *Brain Neoplasms/drug therapy/secondary
MH  - Protein Kinase Inhibitors/therapeutic use
PMC - PMC9622589
COIS- Tony Mok Employment: The Chinese University of Hong Kong Leadership: AstraZeneca, 
      Aurora Tele-Oncology Platform, Lunit, ACT Genomics-Sanomics Group, HUTCHMED Stock 
      and Other Ownership Interests: Aurora Tele-Oncology Platform, HUTCHMED, ACT 
      Genomics-Sanomics Group Honoraria: AstraZeneca, Alpha Biopharma, ACEA 
      Pharmaceutical Research, Amgen, Amoy Diagnostics, BeiGene, Boehringer Ingelheim, 
      Bristol Myers Squibb, Daiichi Sankyo/UCB Japan, Fishawack Facilitate, InMed, 
      Lilly, Merck Sharp & Dohme, Novartis, Origimed, Pfizer, Prime Oncology, Roche, 
      Sanofi Aventis GmbH, Taiho Pharmaceutical, Takeda, Lucence, Medscape, Permanyer 
      Publications, PeerVoice, Physicans' Education Resource, Research to Practice, 
      Shanghai BeBirds Translation & Consulting, Liangyihui Network Technology Co., 
      Ltd, AbbVie, Berry Oncology, Blueprint Medicines, C4 Therapeutics, CStone 
      Pharmaceuticals, Curio Science, D3, Eisai, Gilead Sciences, Gritstone Bio, 
      Guardant Health, touchIME Consulting or Advisory Role: AbbVie, ACEA 
      Pharmaceutical Research, Alpha Biopharma, Amgen, Amoy Diagnostics, AstraZeneca, 
      BeiGene, Berry Oncology, Boehringer Ingelheim, Blueprint Medicines, Bristol Myers 
      Squibb, CStone Pharmaceuticals, Curio Science, Daiichi Sankyo/UCB Japan, Eisai, 
      Fishawack Facilitate, Gritstone Bio, Guardant Health, Hengrui Therapeutics, 
      Ignyta, Incyte, Inivata, IQvia, Lilly, Loxo, Lunit, Merck Serono, Merck Sharp & 
      Dohme, Mirati Therapeutics, Novartis, Pfizer, Puma Biotechnology, Roche, SFJ 
      Pharmaceuticals Group, Takeda, Vertex, Yuhan, Qiming Development (HK) Ltd, D3, C4 
      Therapeutics, G1 Therapeutics, Gilead Sciences, Janssen, geneDecode Research 
      Funding: AstraZeneca (Inst), Boehringer Ingelheim (Inst), Pfizer (Inst), Novartis 
      (Inst), SFJ Pharmaceuticals Group (Inst), Roche (Inst), Merck Sharp & Dohme 
      (Inst), Bristol Myers Squibb (Inst), Xcovery (Inst), G1 Therapeutics (Inst), 
      Merck Serono (Inst), Takeda (Inst) No other potential conflicts of interest were 
      reported.
EDAT- 2022/05/24 06:00
MHDA- 2022/11/01 06:00
PMCR- 2022/05/23
CRDT- 2022/05/23 16:03
PHST- 2022/05/24 06:00 [pubmed]
PHST- 2022/11/01 06:00 [medline]
PHST- 2022/05/23 16:03 [entrez]
PHST- 2022/05/23 00:00 [pmc-release]
AID - JCO.21.02278 [pii]
AID - 10.1200/JCO.21.02278 [doi]
PST - ppublish
SO  - J Clin Oncol. 2022 Nov 1;40(31):3593-3602. doi: 10.1200/JCO.21.02278. Epub 2022 
      May 23.